VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

Sci Adv. 2023 Jun 23;9(25):eadg2339. doi: 10.1126/sciadv.adg2339. Epub 2023 Jun 23.

Abstract

Stringent control of type I interferon (IFN-I) signaling is critical to potent innate immune responses against viral infection, yet the underlying molecular mechanisms are still elusive. Here, we found that Van Gogh-like 2 (VANGL2) acts as an IFN-inducible negative feedback regulator to suppress IFN-I signaling during vesicular stomatitis virus (VSV) infection. Mechanistically, VANGL2 interacted with TBK1 and promoted the selective autophagic degradation of TBK1 via K48-linked polyubiquitination at Lys372 by the E3 ligase TRIP, which serves as a recognition signal for the cargo receptor OPTN. Furthermore, myeloid-specific deletion of VANGL2 in mice showed enhanced IFN-I production against VSV infection and improved survival. In general, these findings revealed a negative feedback loop of IFN-I signaling through the VANGL2-TRIP-TBK1-OPTN axis and highlighted the cross-talk between IFN-I and autophagy in preventing viral infection. VANGL2 could be a potential clinical therapeutic target for viral infectious diseases, including COVID-19.

MeSH terms

  • Animals
  • Autophagy
  • Cell Polarity
  • Interferon Type I* / immunology
  • Mice
  • Protein Serine-Threonine Kinases* / metabolism
  • Transcription Factors
  • Virus Diseases* / immunology

Substances

  • Protein Serine-Threonine Kinases
  • Transcription Factors
  • Ltap protein, mouse
  • Tbk1 protein, mouse
  • Interferon Type I